Project Summary/Abstract The exogenous application of electric currents is an effective method widely used to treat a plethora of clinical conditions and to enhance mental skills including multitasking capability and numerical cognition in healthy humans. Despite the wide use of localized direct current stimulation (DCS) in experimental, clinical and public settings, the molecular bases of its effects in various cell types are unknown. We seek to gain fundamental knowledge about the effects and signals mediating DCS in adult tissues. Therefore, we focus on basic electrophysiology research using a model system based on planarian flatworms, which is amenable to study various DCS modalities and their effects on tissues at systemic and cellular levels. We plan to merge molecular genetics and electrophysiology to define instructive mechanisms underlying cellular responses to DCS. Planarians activate stem cells (SCs) called neoblasts to continually renew adult tissues and are capable of regenerating any part of their body upon injury. Our research team developed a novel strategy based on the external application of DCS of physiological strength to the whole planarian body. We provide compelling evidence that it is possible to use DCS similar to the one used in humans to control collective neoblast behavior in vivo (i.e. regulation of transcription, cell cycle, cell death, differentiation), and induce permanent changes in adult tissue identity without using genetic or pharmacological treatments. The integration of biophysical and genetic information may provide a paradigm shift in the way we approach SC regulation in the adult body and by executing this project we expect to uncover mechanistic insights about this process. A major impact of these studies will be the elucidation of basic mechanisms mediating DCS effects in the complexity of the whole organism to enable the implementation of biomedical approaches to induce selective tissue replacements and control cellular behavior to prevent or treat disease.